Described herein are electromagnetic treatment devices, systems and methods. Some embodiments pertain generally to a method and apparatus for therapeutic and prophylactic treatment of animal and human cells and tissues. In particular, some embodiments pertain to use of non-thermal time-varying electromagnetic fields configured to accelerate the asymmetrical kinetics of the binding of intracellular ions to their respective binding proteins which regulate the biochemical signaling pathways living systems employ to reduce the inflammatory response to injury, and to enhance healing and well-being. Other embodiments pertain to the non-thermal application of repetitive pulse bursts of sinusoidal, rectangular, chaotic or arbitrary waveform electromagnetic fields to instantaneously accelerate ion-buffer binding in signaling pathways in animal and human cells and tissues using ultra lightweight portable coupling devices such as inductors and electrodes, driven by miniature signal generator circuitry that can be incorporated into an anatomical positioning device such as a dressing, bandage, compression bandage, compression dressing; lumbar or cervical back, shoulder, head, neck and other body portion wraps and supports; garments, hats, caps, helmets, mattress pads, seat cushions, beds, stretchers, and other body supports in cars, motorcycles, buses, trains, airplanes, boats, ships and the like.
In some embodiments, the proposed EMF transduction pathway relevant to tissue maintenance, repair and regeneration, begins with voltage-dependent Ca2+ binding to CaM, which is favored when cytosolic Ca2+ homeostasis is disrupted by chemical and/or physical insults at the cellular level. Ca/CaM binding produces activated CaM that binds to, and activates, cNOS, which catalyzes the synthesis of the signaling molecule NO from L-arginine. This pathway is shown in its simplest schematic form in FIG. 1A. FIG. 1A is a schematic summary of the body's primary anti-inflammatory cascade and the proposed manner by which PEMF may accelerate postoperative pain relief. Surgical injury increases cytosolic Ca2+, which activates CaM. PEMF accelerates CaM activation thereby enhancing NO/cGMP anti-inflammatory signaling. PEMF also enhances CaM-dependent PDE activation, which accelerates cGMP inhibition. PEMF dosing must take into account the competing dynamics of NO/cGMP signaling and PDE inhibition of cGMP.
As shown in FIG. 1A, cNOS* represents activated constitutive nitric oxide synthase (cNOS), which catalyzes the production of NO from L-arginine, which, in turn, activates soluble gyanylyl cyclase, sGC. The term “sGC*” refers to activated guanylyl cyclase which catalyzes cyclic guanosine monophosphate (cGMP) formation when NO signaling modulates the tissue repair pathway. “AC*” refers to activated adenylyl cyclase, which catalyzes cyclic adenosine monophosphate (cAMP) when NO signaling modulates differentiation and survival.
According to some embodiments, an EMF signal can be configured to accelerate cytosolic ion binding to a cytosolic buffer, such as voltage dependent Ca2+ binding to CaM, because the rate constant for binding, kon is much greater than the rate constant for unbinding, koff, imparting rectifier-like properties to ion-buffer binding, such as Ca2+ binding to CaM.
Yet another embodiment pertains to application of sinusoidal, rectangular, chaotic or arbitrary waveform electromagnetic signals, having frequency components below about 100 GHz, configured to accelerate the binding of intracellular Ca2+ to a buffer, such as CaM, to enhance biochemical signaling pathways in animal and human cells and tissues. Signals configured according to additional embodiments produce a net increase in a bound ion, such as Ca2+, at CaM binding sites because the asymmetrical kinetics of Ca/CaM binding allows such signals to accumulate voltage induced at the ion binding site, thereby accelerating voltage-dependent ion binding. Examples of therapeutic and prophylactic applications are modulation of biochemical signaling in anti-inflammatory pathways, modulation of biochemical signaling in cytokine release pathways, modulation of biochemical signaling in growth factor release pathways; edema and lymph reduction, anti-inflammatory, post-surgical and post-operative pain and edema relief, nerve, bone and organ pain relief, increased local blood flow, microvascular blood perfusion, treatment of tissue and organ ischemia, brain tissue ischemia from stroke or traumatic brain injury, treatment of neurological injury and neurodegenerative diseases such as Alzheimer's and Parkinson's; angiogenesis, neovascularization; enhanced immune response; enhanced effectiveness of pharmacological agents; nerve regeneration; prevention of apoptosis; modulation of heat shock proteins for prophylaxis and response to injury or pathology.
In some variations the systems, devices and/or methods generally relate to application of electromagnetic fields (EMF), and in particular, pulsed electromagnetic fields (PEMF), including a subset of PEMF in a radio frequency domain (e.g., pulsed radio frequency or PRF), for the treatment of any of the applications disclosed herein in animals and humans, including pain, edema, tissue repair and head, cerebral and neural injury, and neurodegenerative conditions.
Transient elevations in cytosolic Ca2+, from external stimuli as simple as changes in temperature and receptor activation, or as complex as mechanical disruption of tissue, will activate CaM. Once Ca2+ ions are bound, a conformational change will allow CaM bind to and activate a number of key enzymes involved in cell viability and function, such as the endothelial and neuronal constitutive nitric oxide synthases (cNOS); eNOS and nNOS, respectively. As a consequence, NO is rapidly produced, albeit in lower concentrations than the explosive increases in NO produced by inducible NOS (iNOS), during the inflammatory response. In contrast, these smaller, transient increases in NO produced by Ca/CaM-binding will activate soluble guanylyl cyclase (sGC), which will catalyze the formation of cyclic guanosine monophosphate (cGMP). The CaM/NO/cGMP signaling pathway can rapidly modulate blood flow in response to normal physiologic demands, as well as to inflammation. Importantly, this same pathway will also rapidly attenuate expression of cytokines such as interleukin-1beta (IL-1β), and iNOS and stimulate anti-apoptotic pathways in neurons. All of these effects are mediated by calcium and cyclic nucleotides, which in turn regulate growth factors such as basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF), resulting in pleiotrophic effects on cells involved in tissue repair and maintenance. PEMF can also accelerate the inhibition of cGMP by phosphodiesterase (PDE) Improved PEMF signal configurations and treatment regimens are disclosed herein that can minimize the inhibition of cGMP by PDE.
Therefore, a need exists for an apparatus and a method that modulates the biochemical pathways that regulate animal and human tissue response to maximize the rate of cGMP production while minimizing the rate of inhibition of cGMP. In some embodiments, an apparatus incorporates miniaturized circuitry and light weight coil applicators or electrodes to deliver any of the waveforms described herein thus allowing the apparatus to be low cost, portable and, if desired, disposable.